12 3 the citric acid cycle oxidizes acetylcoa l.
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12.3 The Citric Acid Cycle Oxidizes AcetylCoA. Table 12.2. Summary of the citric acid cycle. For each acetyl CoA which enters the cycle: (1) Two molecules of CO 2 are released (2) Coenzymes NAD + and Q are reduced (3) One GDP (or ADP) is phosphorylated

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summary of the citric acid cycle
Summary of the citric acid cycle
  • For each acetyl CoA which enters the cycle:
  • (1) Two molecules of CO2 are released
  • (2) Coenzymes NAD+ and Q are reduced
  • (3) One GDP (or ADP) is phosphorylated
  • (4) The initial acceptor molecule (oxaloacetate) is reformed
slide7

Fates of carbon atoms in the cycle

  • Carbon atoms from acetyl CoA (red) are not lost in the first turn of the cycle
energy conservation by the cycle
Energy conservation by the cycle
  • Energy is conserved in the reduced coenzymes NADH, QH2 and one GTP
  • NADH, QH2 can be oxidized to produce ATP by oxidative phosphorylation
the citric acid cycle can be a multistep catalyst
The Citric Acid Cycle Can Be a Multistep Catalyst
  • Oxaloacetate is regenerated
  • The cycle is a mechanism for oxidizing acetyl CoA to CO2 by NAD+ and Q
  • The cycle itself is not a pathway for a netdegradation of any cycle intermediates
  • Cycle intermediates can be shared with other pathways, which may lead to a resupply or net decrease in cycle intermediates
1 citrate synthase
1. Citrate Synthase
  • Citrate formed from acetyl CoA and oxaloacetate
  • Only cycle reaction with C-C bond formation
stereo views of citrate synthase
Stereo views of citrate synthase

(a) Open conformation

(b) Closed conformation

Product citrate (red)

2 aconitase
2. Aconitase
  • Elimination of H2O from citrate to form C=C bond of cis-aconitate
  • Stereospecific addition of H2O to cis-aconitate to form 2R,3S-Isocitrate
three point attachment of prochiral substrates to enzymes
Three point attachment of prochiral substrates to enzymes
  • Chemically identical groups a1 and a2 of a prochiral molecule can be distinguished by the enzyme
3 isocitrate dehydrogenase
3. Isocitrate Dehydrogenase
  • Oxidative decarboxylation of isocitrate toa-ketoglutarate (a-kg) (a metabolically irreversible reaction)
  • One of four oxidation-reduction reactions of the cycle
  • Hydride ion from the C-2 of isocitrate is transferred to NAD(P)+ to form NAD(P)H
  • Oxalosuccinate is decarboxylated to a-kg
4 the a ketoglutarate dehydrogenase complex
4. The a-Ketoglutarate Dehydrogenase Complex
  • Second decarboxylation (CO2 released)
  • Energy stored as reduced coenzyme, NADH
structure of a ketoglutarate dehydrogenase complex
Structure of a-Ketoglutarate dehydrogenase complex
  • Similar to pyruvate dehydrogenase complex
  • Same coenzymes, identical mechanisms
  • E1 - a-ketoglutarate dehydrogenase (with TPP)
  • E2 - succinyltransferase (with flexible lipoamide prosthetic group)
  • E3 - dihydrolipoamide dehydrogenase(with FAD)
5 succinyl coa synthetase
5. Succinyl-CoA Synthetase
  • Free energy in thioester bond of succinyl CoA is conserved as GTP (or ATP in plants, some bacteria)
fig 12 9
Fig 12.9
  • Mechanism of succinyl-CoA synthetase (continued on next slide)
6 the succinate dehydrogenase sdh complex
6. The Succinate Dehydrogenase (SDH) Complex
  • Located on the inner mitochondrial membrane (other components are dissolved in the matrix)
  • Dehydrogenation is stereospecific; only the trans isomer is formed
  • Substrate analog malonate is a competitive inhibitor of the SDH complex
succinate and malonate
Succinate and malonate
  • Malonate is a structural analog of succinate
  • Malonate binds to the enzyme active site, and is a competitive inhibitor
structure of the sdh complex
Structure of the SDH complex
  • Complex of several polypeptides, a covalently bound FAD prosthetic group and 3 iron-sulfur clusters
  • Electrons are transferred from succinate to ubiquinone (Q), a lipid-soluble mobile carrier of reducing power
  • FADH2 generated is reoxidized by Q
  • QH2 is released as a mobile product
7 fumarase
7. Fumarase
  • Stereospecific trans addition of water to the double bond of fumarate to form L-malate
reduced coenzymes fuel the production of atp
Reduced Coenzymes Fuel the Production of ATP
  • Each acetyl CoA entering the cycle nets:
  • (1)3 NADH
  • (2) 1 QH2
  • (3) 1 GTP (or 1 ATP)
  • Oxidation of each NADH yields 2.5 ATP
  • Oxidation of each QH2 yields 1.5 ATP
  • Completeoxidation of 1 acetyl CoA = 10 ATP
nadh fate in anaerobic glycolysis
NADH fate in anaerobicglycolysis
  • Anaerobicglycolysis
  • NADH produced by G3PDH reaction is reoxidized to NAD+ in the pyruvate to lactate reaction
  • NAD+ recycling allows G3PDH reaction (and glycolysis) to continue anaerobically
nadh fate in aerobic glycolysis
NADH fate in aerobicglycolysis
  • Glycolytic NADH is not reoxidized via pyruvate reduction but is available to fuel ATP formation
  • Glycolytic NADH (cytosol) must be transferred to mitochondria (electron transport chain location)
  • Two NADH shuttles are available (next slide)
nadh shuttles
NADH shuttles
  • Malate-aspartateshuttle (most common)

One cytosolic NADH yields ~ 2.5 ATP (total 32 ATP/glucose)

  • Glycerolphosphateshuttle

One cytosolic NADH yields ~1.5ATP (total 30 ATP/glucose)

12 6 regulation of the citric acid cycle
12.6 Regulation of the Citric Acid Cycle
  • Pathway controlled by:
  • (1) Allosteric modulators
  • (2) Covalent modification of cycle enzymes
  • (3) Supply of acetyl CoA
  • (4) Regulation of pyruvate dehydrogenase complex controls acetyl CoA supply
fig 12 12 regulation of the pdh complex
Fig 12.12Regulation of the PDH complex
  • Increased levels of acetyl CoA and NADH inhibit E2, E3 in mammals and E. coli